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Conditioning fat for the future: adipose tissue expansion during childhood

Meln, Irina

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Obesity has become a global health problem for both children and adults. White adipose tissue (WAT) displays unique plasticity upon excessive feeding by expanding its mass through proliferation and differentiation of resident adipocyte progenitor cells (AP). Studies have shown that excessive accumulation of WAT is pre-determined during early childhood. However, mechanisms of the body weight programming and effect of WAT expansion during childhood on metabolic disease risk later in life are still elusive. In order to investigate regulation of AP expansion by obesogenic diet, we established a diet-induced obesity model. We observed a rapid gain in body weight and increased accumulation of WAT already one week after high-fat diet (HFD) feeding in young, sexually immature female mice, but not adult mice. Moreover, HFD induced WAT growth via proliferation of APs and partially through mature adipocyte hypertrophy. Employing an isocaloric, pair feeding approach, we found that dietary fat content is able to induce proliferation of APs, while the amount of consumed calories seems to promote inflammation. Moreover we demonstrated that AP proliferation could occur without initial hypertrophy of mature adipocytes. Although we demonstrated that the concentration of insulin-like growth factor 1 (IGF-1) was regulated by calorie load as little as 2 days of HFD, it was not changed upon isocaloric HFD thus could not fully explain the proliferation we observed in APs. Additionally, we found lipids transiently increased after feeding and could be potentially involved in AP activation. In order to identify genes involved in regulating AP responses in the niche upon excessive feeding during childhood, we performed gene expression profiling from whole tissue and specific cellular subpopulations of WAT. A large portion of the differentially expressed genes from WAT profiles were associated with key events in tissue remodeling and cell-to-cell communication, such as inflammation, cytokine production, and extracellular matrix proteins/remodeling enzymes. In order to functionally validate candidate genes, a novel co-culture system with APs and feeder niche-like cells was established to mimic WAT physiological conditions. This system was used for siRNA screening by high-content microscopy to identify alterations in cell proliferation and differentiation. Several gene targets related to increased proliferation of APs in response to HFD feeding have been validated including epithelial membrane protein 1 (EMP1), which known to play a role in cell junctions. EMP1 modulation in feeder cells (siRNA mediated knockdown or overexpression) altered AP-derived colony growth. Our results suggested that high fat feeding induces activation of the network of cell-cycle related genes triggering AP proliferation in early development.

Item Type: Dissertation
Supervisor: Lohmann, Prof. Dr. Ingrid
Place of Publication: Heidelberg, Germany
Date of thesis defense: 21 December 2016
Date Deposited: 17 Aug 2017 09:44
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 500 Natural sciences and mathematics
570 Life sciences
Controlled Keywords: Obesity, White adipose tissue, Adipocyte progenitor cells, High-fat diet, Gene expression profiling, Co-culture system
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